Catalytic inhibition of DNA topoisomerase II by N-benzyladriamycin (AD 288).
Catalytic inhibition of DNA topoisomerase II by N-benzyladriamycin (AD 288).
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N-benzyladriamycin (AD 288) 对 DNA 拓扑异构酶 II 的催化抑制。
DOI：
10.1016/s0006-2952(00)00472-x
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发表时间：
2000
影响因子：
5.8
通讯作者：
Sweatman,TW
中科院分区：
文献类型：
--
作者：
Lothstein,L;Suttle,DP;Roaten,JB;Koseki,Y;Israel,M;Sweatman,TW
n -苄ladriamycin （ad288）是一种高度亲脂的半合成阿霉素（DOX）同族物。DOX通过稳定拓扑异构酶II/DNA可切割复合物刺激双链DNA断裂，而AD 288是拓扑异构酶II的催化抑制剂，能够阻止拓扑异构酶II对DNA的活性。AD 288抑制拓扑异构酶ii催化的动质体DNA连接网络十烯醛化所需的浓度与DOX相当。然而，ad288不能稳定可切割复合物的形成或刺激拓扑异构酶ii介导的DNA切割。此外，AD 288抑制依托泊苷形成可切割配合物呈浓度依赖性。人CCRF-CEM细胞和小鼠J774.2细胞通过降低拓扑异构酶II活性表现出对DOX、替尼普苷或3′-羟基-3′-脱氨基多柔比星的抗性，但仍对AD 288敏感。这些研究表明，AD 288通过阻止拓扑异构酶II与DNA的初始非共价结合来抑制拓扑异构酶II的活性。由于AD 288是一个有效的DNA插入物，催化抑制是通过禁止酶进入DNA结合位点来实现的。这些结果还表明，对DOX的氨基糖的特异性取代可以改变拓扑异构酶II抑制的机制。
N-Benzyladriamycin (AD 288) is a highly lipophilic, semi-synthetic congener of doxorubicin (DOX). Unlike DOX, which stimulates double-stranded DNA scission by stabilizing topoisomerase II/DNA cleavable complexes, AD 288 is a catalytic inhibitor of topoisomerase II, capable of preventing topoisomerase II activity on DNA. The concentration of AD 288 required to inhibit the topoisomerase II-catalyzed decatenation of linked networks of kinetoplast DNA was comparable to that for DOX. However, AD 288 did not stabilize cleavable complex formation or stimulate topoisomerase II-mediated DNA cleavage. In addition, AD 288 inhibited the formation of cleavable complexes by etoposide in a concentration-dependent manner. Human CCRF-CEM cells and murine J774.2 cells exhibiting resistance against DOX, teniposide, or 3′-hydroxy-3′-deaminodoxorubicin through reduced topoisomerase II activity remained sensitive to AD 288. These studies suggest that AD 288 inhibits topoisomerase II activity by preventing the initial non-covalent binding of topoisomerase II to DNA. Since AD 288 is a potent DNA intercalator, catalytic inhibition is achieved by prohibiting access of the enzyme to DNA binding sites. These results also demonstrate that specific substitutions on the aminosugar of DOX can alter the mechanism of topoisomerase II inhibition.
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影响因子：
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11.2
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
5.8
作者：
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通讯作者：
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